Effects of propafenone and 5-hydroxy-propafenone on hKv1.5 channels

Abstract

1. The goal of this study was to analyse the effects of propafenone and its major metabolite, 5-hydroxy-propafenone, on a human cardiac K⁺ channel (hKv1.5) stably expressed in Ltk⁻ cells and using the whole-cell configuration of the patch-clamp technique.

2. Propafenone and 5-hydroxy-propafenone inhibited in a concentration-dependent manner the hKv1.5 current with K_D values of 4.4±0.3 μM and 9.2±1.6 μM, respectively.

3. Block induced by both drugs was voltage-dependent consistent with a value of electrical distance (referenced to the cytoplasmic side) of 0.17±0.55 (n=10) and 0.16±0.81 (n=16).

4. The apparent association (k) and dissociation (l) rate constants for propafenone were (8.9±0.9)×10⁶ M⁻¹ s⁻¹ and 39.5±4.2 s⁻¹, respectively. For 5-hydroxy-propafenone these values averaged (2.3±0.3)×10⁶ M⁻¹ s⁻¹ and 21.4±3.1 s⁻¹, respectively.

5. Both drugs reduced the tail current amplitude recorded at −40 mV after 250 ms depolarizing pulses to +60 mV, and slowed the deactivation time course resulting in a `crossover' phenomenon when the tail currents recorded under control conditions and in the presence of each drug were superimposed.

6. Both compounds induced a small but statistically significant use-dependent block when trains of depolarizations at frequencies between 0.5 and 3 Hz were applied.

7. These results indicate that propafenone and its metabolite block hKv1.5 channels in a concentration-, voltage-, time- and use-dependent manner and the concentrations needed to observe these effects are in the therapeutical range.

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